Introduction

Epigenetics is the study of the changes that occur on top of the DNA without changing the genome sequence, but still affect the expression of our genes and thereby shape our phenotype. This is the reason why even identical twins, which have almost the same genome sequence, are different from each other: due to their distinct epigenome.

Epigenetic traits, unlike the genome, are configured all along development. They are flexible and reversible. This is the reason why we can have so many distinct cells in our body, each with its own shape, size and molecular characteristics that determine their function. And that is also why scientists can reverse almost any somatic cell into a pluripotent cell (cells that are able to differentiate, or mature, into the three primary groups of cells that form a human being: ectoderm, endoderm and mesoderm); important for cell therapy.

Nevertheless, the epigenome is also heritable across generations. It is influenced by the dietary habits and life styles of our parents. However, they can be reversed by our own habits and pass the changes to our children.

Epigenetic changes

The most important epigenetic changes in an organism include DNA methylation and histone modifications. To get a clearer idea about them, let's discuss them in detail.

DNA methylation

DNA methylation is essentially the addition of a methyl group to specific regions of the DNA sequence. When DNA methylation occurs near the sequence of a gene, the expression of that gene is drastically repressed. DNA methylation is essential for normal development. It is usually deleted during the formation of the zygote but is restored in the embryo around the time of implantation. Most DNA methylations play important roles in genomic imprinting and X chromosome inactivation, and when dysregulated, they contribute to serious diseases such as cancer.

Histone modification

Histone modifications involve a series of chemical changes that take place in proteins called histone proteins. These proteins serve as pulleys for the long DNA that is packaged into our cells. The more packaged a gene region is, the more difficult it is to express it and define a phenotype. The most well-known histone modifications include histone acetylation and methylation. These modifications not only change the chromatin structure, but also determine the recruitment of other proteins to the DNA to activate or deactivate certain genes and even repair damaged areas of the genome. Thus, histone modifications are important for the correct expression of genes and the avoidance of cells with abnormal genomic information. They are associated with a number of diseases and their condition can be used to monitor the effectiveness of medical treatment.

What does it look like at the molecular level?

The expression of a gene can be regulated during its transcription into RNA or during its translation into proteins. A gene that is prevented from producing proteins cannot perform its function in a cell or express its phenotypic trait in an organism. This impacts a variety of crucial biological processes, including normal development or disease progression.

Epigenetics includes at least 3 different mechanisms that regulate the expression of genes. Epigenetics exerts regulation via covalent modifications (DNA methylation and histone modifications), transcription factors and microRNAs.

Covalent modifications

As explained above, covalent modifications include DNA methylation and hydroxymethylation at cytosine residues in specific regions of the genome called CpG sites. They also include histone modifications such as lysine and arginine methylation and acetylation, as well as serine and threonine phosphorylation and lysine ubiquitination and sumoylation. Covalent modifications exert control over the genome by:

1. Remodel the chromatin structure, making genes either less or more accessible for expression and/or by
2. Recruitment or prevention of binding of proteins required for expression of the genome.

The mechanism of histone modifications is less clear than that of DNA methylation. While DNA methylation often acts as a repressive or silencing factor of gene expression, histone modifications likely function in different ways. An acetylated histone at one location in the genome can have opposite effects than an acetylated histone at another location in the genome. Likewise, methylation on one histone lysine may have a different effect than methylation of another lysine on the same histone. Covalent modifications are incorporated by proteins called writers and removed again by proteins called erasers. Drugs that inhibit writer or eraser proteins are now used to treat certain types of cancer. Other histone changes linked to other diseases and cancers have yet to be discovered.

Transcription factors (TF)

Transcription factors (TF) are another mechanism of epigenetic regulation. They can act as positive or negative regulators of gene expression. Transcription factors bind to DNA sequences located in specific regions of the genome. These sequences can be either transcription enhancers or insulators that have a negative or positive effect on transcription. Enhancers serve as hubs for transcription factors that promote the expression of a gene. Insulators can either abolish the suppressive effect of DNA methylation or the promoting effect of enhancers.

MircoRNAs (miRNAs)

MicroRNAs (miRNAs) are RNA molecules with 17-25 nucleotides that do not code for any protein and are therefore never translated. However, they exert a suppressive effect on the expression of a number of genes. It was calculated that each miRNA can downregulate the translation of about 100 to 200 messenger RNAs (mRNAs: RNAs that code for proteins). MicroRNAs work by pairing with mRNAs, which in most cases results in degradation of the mRNA or, in some other cases, downregulation of its translation into proteins.

Conclusion

At MoleQlar Analytics there are experts who work on the interaction of proteins and histone modifications. Together with the pharmaceutical industry, clinics and other partners, we want to decipher the unknown connections between these molecular structures in humans.